Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33
Susana Castanhinha1, Rebekah Sherburn2, Simone Walker2
1Department of Respiratory Paediatrics, Royal Brompton Hospital, London, United Kingdom.
Background:
The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored.
Objective:
We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33.
Methods:
Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model.
Results:
Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13(+) innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13(+) ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2(-/-) mice lacking a functional receptor for IL-33.
Conclusion:
Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.
Insights
Interleukin-33 (IL-33) plays a key role in severe asthma with fungal sensitization (SAFS) in children, driving steroid-resistant airway hyperresponsiveness. Targeting IL-33 may offer a new therapeutic strategy for pediatric SAFS.
Area of Science:
- Immunology
- Allergy and Asthma Research
- Pediatric Respiratory Medicine
Background:
- The underlying mechanisms of severe asthma with fungal sensitization (SAFS) remain unclear.
- The role of Interleukin-33 (IL-33) in fungal sensitization, despite its known importance in fungus-induced asthma exacerbations, is unexplored.
Purpose of the Study:
- To investigate whether IL-33 mediates fungal sensitization in children diagnosed with severe, therapy-resistant asthma.
- To explore the immunopathological features associated with SAFS in pediatric patients.
Main Methods:
- Eighty-two children with severe therapy-resistant asthma were evaluated, with 38 diagnosed with SAFS based on allergic responses to common fungi.
- Clinical data, airway immunopathology, and serum IgE levels were assessed.
- A neonatal mouse model was used to compare the effects of chronic exposure to Alternaria alternata versus house dust mite, examining IL-33 levels, immune cell populations, and airway hyperresponsiveness (AHR).
Main Results:
- Children with SAFS exhibited earlier symptom onset, higher total IgE levels, and a greater need for oral steroid maintenance therapy.
- SAFS was significantly associated with elevated IL-33 levels in the airways.
- In mice, Alternaria alternata exposure led to increased IL-33, IL-13-producing innate lymphoid cells (ILC2s), TH2 cells, and steroid-resistant AHR, which were IL-33-dependent.
Conclusions:
- Pediatric SAFS is linked to increased IL-33 levels and a higher requirement for oral steroid treatment.
- IL-33 drives fungal-sensitization-induced increases in ILC2s, TH2 cells, and steroid-resistant AHR.
- IL-33 emerges as a potential novel therapeutic target for managing pediatric SAFS.
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